tbuckley/cabot-search huggingface dataset:
Single-stranded linear amplification library preparation method for highly sensitive and low input amount ctDNA detection.
Authors: Juan Hu, Meihong Chen, Zihao Li, Shanshan Xiao, Tao Wang
Journal: Journal of Clinical Oncology (2023)

e15096 Background: Detection of circulating tumor DNA (ctDNA) or minimum residual disease (MRD) through somatic variant identifications in plasma samples has emerged as a promising approach for monitoring the clinical outcomes after surgical resections or other therapies. However, due to very low ctDNA levels in the early-stage cancers and tumor remissions after therapies, or low plasma volumes and DNA degradation caused low qualities in clinical practice, to sensitively identify somatic mutations with low allele frequencies in those samples remains a challenging technology task. Methods: In this study, we developed a single-stranded, linear amplification based library preparation sequencing (SLA-Seq) method. In the experimental workflow, double stranded molecular templates will be converted into single strands to construct libraries, thus minimize the loss of irregular double stranded DNA molecules. Adapter ligation was carried out in two steps. During the first step, P7 adapters with unique molecular identifiers(UMI) were ligated to the 3’ end of the molecular templates, and the DNA molecules were amplified by linear amplification to improve the DNA utilization efficiency. In the second step, P5 adapters were ligated to the linear amplified PCR products, then amplified by the pre-PCR. The pre-library was enriched by hybridization and magnetic-beads capturing and then subjected to high-throughput sequencing. 30ng of the cfDNA reference standard samples containing mutations of 0.3% and 0.1% allele frequencies were used to validate the performance. Results: In the SLA-Seq method, adapter sequences were carefully optimized to eliminate adapter dimers and thus improved the DNA ligation efficiency. Compared with the double-stranded library preparation method, SLA-seq showed overall higher effective depths after removing duplications if the same start amount of the DNA was used, which indicated that the higher DNA utilization rate was achieved. To evaluate the performance, we applied SLA-Seq on 11 reference standard samples with only 30ng start amount DNA. Among them, 6 samples were diluted to 0.3% allele frequency and 5 samples were diluted to 0.1% allele frequency. Totally they had 24 and 35 mutations, respectively. The sensitivity at the 0.3% allele frequency was 100% (24/24) and it was 94.29% (33/35) at the 0.1% mutation level, which also showed the higher sensitivity achieved by SLA-Seq than double-stranded library preparation method. Conclusions: We developed a single-stranded, linear amplification based library preparation method to improve difficult sample situations such as low input amount and low qualities, and achieved high single site sensitivity at the 0.1% allele frequency. Such features imply SLA-Seq has important clinical significance in the ctDNA/MRD detection.
Efficacy and safety of regorafenib and PD-1 combined with cryoablation in the treatment of advanced hepatocellular carcinoma after second-line targeted therapy.
Authors: Yan Chen, Huifang Kong, Sihao Wang, Wei Zhang, Xiujuan Chang, Jiagan Huang, Zheng Dong, Xudong Gao, Bin Yang, Huixin Zhang, Bailong Zhang, Yongping Yang, Zhen Zeng
Journal: Journal of Clinical Oncology (2023)

e16151 Background: Targeted therapy is the most effective therapeutic approach for middle and late-stage hepatocellular carcinoma (HCC). Regorafenib or PD-1 as a second-line treatment of patients with advanced HCC has achieved good results. Argon-helium cryoablation is one commonly used method for local ablation of liver cancer. Whether systemic therapy combined with local therapy can benefit patients with advanced liver cancer is a hot topic. This study is aimed to investigate the efficacy and safety of regorafenib and PD-1 combined with cryoablation in the treatment of patients with advanced HCC after the failure of second-line targeted treatment. Methods: In this retrospective study, unresectable HCC patients received regorafenib and PD-1combined with cryoablation after the failure of second-line targeted treatment from January 2019 to December 2021 were enrolled. Depending on whether combining local therapy, patients were grouped as RP (regorafenib and PD-1), or RPC groups (regorafenib and PD-1 combined with cryoablation). Objective response rate (ORR), disease control regorafenib rate (DCR), progression free survival (PFS), and safety were recorded. The PFS was defined as the time from the first dose of RP, or from the time of using RPC until disease progression or death. Results: A total of 50 patients were reviewed, including 21 patients in RP group and 29 patients in RCP group. One patient was classified as Barcelona Clinic Liver Cancer (BCLC) stage B and 20 patients were at BCLC stage C in RP group, while one patient was at BCLC stage B and 28 patients were at BCLC stage C in RPC group. The ORR and DCR were 4.8% and 23.8% in PR group respectively, and 31.0% and 69.0% in RPC group respectively. The 6-month PFS rate of RP group and RPC group was 14.3% and 53.6% respectively. Thirteen (61.9%) and eighteen (62.1%) patients experienced adverse events (AEs) in two groups respectively. Two (9.5%) and three (10.7%) patients experienced grade 3 AEs that occurred in RP group and RPC group respectively. The most frequency AE was hand-foot-skin reaction in both groups (58.0% and 50.0%, respectively). No patient discontinued regorafenib and PD-1 due to AE in these two groups. Conclusions: Regorafenib and PD-1 combined with cryoablation showed potential anti-tumor effect and tolerance on unresectable HCC after the failure of second-line targeted treatment. [Table: see text]
Immunotherapy versus tyrosine kinase inhibitors in advanced hepatocellular carcinoma in first-line setting: A systematic review and meta-analysis of randomized controlled trials.
Authors: Ana Carolina Carolina Marin Comini, Isadora Martins de Sousa, Pedro Cotta Abrahão Reis, Bruno Murad Carvalho, Marcos Pedro Guedes Camandaroba
Journal: Journal of Clinical Oncology (2023)

e16132 Background: Hepatocellular carcinoma has a high mortality rate, with an overall 5-year survival of less than 20%. Whether the use of immune checkpoint inhibitors (ICI) is superior to tyrosine kinase inhibitors (TKI) as a first-line therapy remains unclear. Methods: We performed a systematic review and meta-analyses of randomized clinical trials (RCTs) to compare ICI, in monotherapy or combined with TKI or anti-VEGF monoclonal antibody in naïve treatment. We searched Embase, PubMed and Cochrane Library databases from inception to November 2022. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS), Overall Response Rate (ORR) and Treatment Related Adverse Events (TRAE). Using a random-effects model, statistical analysis was performed with RevMan 5.4 version for proportions and risk ratios for binary outcomes from comparative studies. Results: We included 10 RCTs comprising 6097 patients in the final analysis, 2554 in ICI monotherapy, 1096 in ICI with anti-VEGF and 2447 in ICI with TKI. The use of ICI, alone or in combination therapy, was associated with a better OS (HR 0.77; 95% CI 0.69–0.85; p&lt; 0.00001; I²=46%) and PFS (HR 0.77; 95% CI 0.64-0.92, p=0.005; I²= 85%). In the ICI monotherapy subgroup, there was a statistical difference to TKI in OS (HR 0.82; 95% CI 0.75-0.91; p=0.0001; I² = 0%). Although there was a higher ORR in all ICI groups (RR 2.56; 95% CI 1.89-3.46; p&lt;0.00001, I²=68%), TRAE Grades 3-4 (RR 0.85; 95% CI 0.61-1.18; p=0.33; I²=96%) presented no difference when compared with TKI. Conclusions: Our findings suggest that the use of ICI, alone or in combination with TKI or anti-VEGF, is a superior option for first-line therapy for advanced hepatocellular carcinoma, improving OS, PFS, and ORR without increasing treatment toxicity. These results are important for guiding clinical decision-making and further research in this field.
Impact of sex on the efficacy of first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus Y90-radioembolization in patients with metastatic colorectal cancer: An exploratory, retrospective analysis of the phase III SIRFLOX trial.
Authors: Kathrin Heinrich, Volker Heinemann, Benedikt Westphalen, Osman Oecal, Guy A. Van Hazel, Peter Gibbs, Max Seidensticker, Jens Ricke, Ricarda Seidensticker
Journal: Journal of Clinical Oncology (2023)

3564 Background: Clinical trials in metastatic colorectal cancer (mCRC) investigating systemic and local treatment options are usually conducted irrespective of sex. However, sex-associated differences relating to safety and efficacy in the treatment of mCRC are of gaining interest. Methods: The SIRFLOX trial investigated the efficacy and safety of adding radioembolization using yttrium-90 resin microspheres (SIRT) to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)–based chemotherapy in patients with previously untreated mCRC comparing it to standard treatment with FOLFOX-based chemotherapy. In this post-hoc analysis, the study population was stratified for sex (male versus female) using Propensity Score Matching (PSM) with baseline variables with difference (p-value &lt; 0.20) in a gender specific comparison serving as matching covariates (age, BSA, sidedness, bilirubin). Groups were matched in a 1:1 ratio, with the nearest calculated propensity logit, with a caliper width of ≤0.20 of the SD of the propensity score logit. Evaluated efficacy endpoints were progression-free survival (PFS, primary endpoint of the trial) and overall survival (OS). Results: 356 (67.2%) male and 173 (32.6%) female patients were randomized and treated in the SIRFLOX trial. In the overall study population, there was no difference regarding PFS or OS between male and female patients. No difference in PFS and OS between male (n = 101) and female (n = 101) patients could be observed independently of treatment arm. After PSM, female patients showed significant benefit regarding PFS from SIRT + chemotherapy compared to chemotherapy alone (12.2 [9.9-17] vs. 9.9 [7.5-12.7], p = 0.047) that translated into a trend to longer OS (27.3 [25.6-36.5] vs. 23.7 [17.8-28.8] months, p = 0.094, HR 0.68 [0.43-1.10]) while male patients did not show a difference regarding PFS and OS between treatment arms (p = 0.170, HR 1.41 [0.87-2.10]). In the experimental arm, female patients had significantly longer OS compared to male patients (27.3 [25.6-36.5] vs. 21.0 [17.9-26.7] months, p = 0.031, HR 0.64 [0.42-0.96]). Sex did not impact on OS in the chemotherapy arm (p = 0.410, HR 1.22 [0.76-2.02]). Conclusions: In the SIRFLOX trial, female patients seem to benefit from the addition of SIRT to chemotherapy regarding PFS and OS. This was not observed in male patients. To our knowledge, this is the first analysis to show sex-differences in the application of SIRT in patients with mCRC. Our results support the development of specific protocols according to sex. Clinical trial information: NCT00724503 .
Homologous recombination-related (HRR) gene mutations in patients with glioma and their relevance to genomic characteristics, tumor mutation burden (TMB), and prognosis.
Authors: Zhiming Zheng, Mengmeng Li, Qin Zhang, Ningning Luo, Yingxue Qi, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2023)

e14023 Background: Homologous Recombination Repair (HRR) is one of the core repair methods for DNA double strand damage and the mutations of HRR pathway gene may be the main cause of many cancers. However, there is little research on the potential correlation between the molecular characteristics of HRR pathway genes and glioma. Our study explored HRR gene mutations in glioma patients and its relevance to genomic characteristics, tumor mutation burden (TMB) and prognosis. Methods: Samples from 367 glioma patients with a median age of 46 were detected by 551-gene panel or whole-exome sequencing (WES), and the WES data of 894 glioma patients were extracted from TCGA database ( http://cancergenome.nih.gov ). Among 367 glioma patients, 151 patients occurred HRR somatic mutations. Among them, 47.68% (72/151) patients carried HRR related pathogenic mutation (P/LP), and 52.32% (79/151) patients carried HRR benign/likely benign/variant of uncertain significance mutations (B/LB/VUS). The patients were divided into two groups according to whether patients carried HRR related pathogenic mutation, HRR P/LP group (72) and Non-HRR P/LP group (295). The differences of genomic characteristics, TMB and prognosis between HRR P/LP group and Non-HRR P/LP group were analyzed. Results: In 151 glioma patients harboring HRR somatic mutations, PTEN had the highest mutation frequency (49%; 74/151), followed by CHEK2, DNMT3A, BRCA2 and ATM, with mutation frequency of 11% (17/151), 10% (15/151), 9% (14/151）and 9% (14/151). Patients of HRR P/LP group and HRR B/LB/UVS group showed a significant difference at HRR pathway genes, including PTEN, RAD50, MSH6 and RAD21. In addition, differences of non-HRR pathway genes in HRR P/LP group and Non-HRR P/LP group were found. The mutation frequency of these differential genes was generally high in HRR P/LP group. However, compared to Non-HRR P/LP group, the mutation frequency of IDH1 in HRR P/LP group was significantly higher (Non-HRR P/LP 32% VS HRR P/LP 10%; P＜0.0001). The TMB value in Non-HRR P/LP group was significantly higher than that in HRR P/LP group (P＜0.0001), and the same trend of TMB in two groups was discovered in TCGA cohort (P＜0.0001). Importantly, a significant difference of overall survival (OS) in TCGA database was found between HRR P/LP group and Non-HRR P/LP group (P＜0.0001, HR =2.17, 95%CI: 1.54-3.06), and the median OS were 17.6 and 34.9 months, respectively. Conclusions: This study showed HRR pathway genes status was significantly related to the genomic characteristics, TMB and prognosis of glioma patients. Compared to patients in HRR P/LP group, patients in Non-HRR P/LP group had higher mutation frequency of IDH1, lower TMB value and better prognosis. The relationship between HRR pathway genes and glioma needs to be further explored.
Racial and socioeconomic disparities in time to chemotherapy and survival in patients with pancreatic cancer.
Authors: Shivani Shah, James Rock, Rodney E. Wegner, Dulabh K. Monga
Journal: Journal of Clinical Oncology (2023)

4100 Background: Pancreatic cancer is traditionally known to be an aggressive malignancy, requiring timely diagnosis and treatment, including chemotherapy and/or surgery. Prior studies have evaluated variances in overall survival (OS) based on race or income; however, research regarding time to treatment based on racial and socioeconomic disparities is underwhelmingly studied. Our project sought to evaluate the impact of race and income on time to chemotherapy and OS in pancreatic cancer patients receiving neoadjuvant or adjuvant chemotherapy. Methods: The National Cancer Database (NCDB) from 2004-2020 was reviewed for patients with a diagnosis of pancreatic cancer, including all types and stages. Exclusion criteria included: no documented income level, time to first treatment surgery, or time to chemotherapy. Our patient population was then separated into two cohorts: neoadjuvant and adjuvant. Income level was stratified into the following: &lt; $30,000, $30,000-34,999, $35,000-$45,999, and &gt; $46,000. Race was also noted. We utilized a logistic regression to identify factors associated with longer time to chemotherapy (using median time to chemotherapy as a benchmark for early or later initiation of chemotherapy). A Cox proportional hazards model was used to identify factors associated with worse survival. A p-value &lt; 0.05 was deemed significant. Results: Our final sample size included 64,640 patients. 6,887 (10.6%) of patients had an income less than $30,000. 55,340 (85.6%) of patients were Caucasian, 6,379 (9.9%) patients were African American, and 172 (0.002%) were American Indian. 18,679 (28.9%) received neoadjuvant chemotherapy, and 45,961 (71.1%) received adjuvant chemotherapy. Median time to chemotherapy was 27 [0-2048] days and 71 [0-1895] days in the neoadjuvant and adjuvant cohorts, respectively. Within both cohorts, income &gt; $46,000 was noted to have significantly earlier time to chemotherapy compared to lower income levels. Those privately insured had significantly earlier time to chemotherapy compared to uninsured. The African American population was associated with a later time to first chemotherapy in comparison to Caucasians in both subgroups. A significantly less OS in the African American population was appreciated in the neoadjuvant cohort (HR 0.92, p-value 0.02), but not the adjuvant cohort. Conclusions: Our retrospective analysis emphasizes that minorities and/or those with a poor socioeconomic status have significant delay in time to chemotherapy in the neoadjuvant and adjuvant setting. Within the African American neoadjuvant cohort, a significantly worse OS was highlighted. This study emphasizes racial and socioeconomic disparities in our healthcare system. Limitations of our study include its retrospective nature and no information regarding the type of surgery the patients received, which could further account for differences in time to chemotherapy.
UP-NEXT (GOG-3049/ENGOT-Ov71-NSGO-CTU): A study of upitifamab rilsodotin (UpRi), a NaPi2b-directed antibody drug conjugate (ADC), in platinum-sensitive recurrent ovarian cancer.
Authors: Debra L. Richardson, Philipp Harter, David M. O'Malley, Antonio Gonzalez Martin, Thomas J. Herzog, Caroline Rogalski, Rita Lemming, Erika Keeton, Robert Allen Burger, Mansoor Raza Mirza
Journal: Journal of Clinical Oncology (2023)

TPS5614 Background: UpRi is a first-in-class NaPi2b-targeting ADC with a novel scaffold-linker-payload that enables high drug-to-antibody ratio and controlled bystander effect. NaPi2b is a sodium-dependent phosphate transporter protein broadly expressed in high-grade serous ovarian cancer (HGSOC) with limited expression in healthy tissues. It is estimated that the majority of HGSOCs have high NaPi2b expression. Studies are being conducted to evaluate UpRi safety and efficacy in platinum-resistant ovarian cancer (PROC), but there remains an unmet need in the maintenance setting for patients with recurrent platinum-sensitive ovarian cancer (PSOC), particularly for patients who have received prior maintenance therapy, are at high-risk of early relapse, and where close monitoring after platinum-based therapy would generally be considered preferable. Methods: UP-NEXT is a Phase 3 study evaluating UpRi monotherapy as post-platinum maintenance treatment in recurrent PSOC, enrolling patients with NaPi2b-positive tumors (defined as TPS ≥75). Patients must have received 2-4 prior lines of platinum containing chemotherapy, achieved a partial or complete response in their penultimate platinum regimen, and progressed &gt;6 months after completion of the last dose of platinum in the penultimate regimen. Patients may be enrolled if their best response to the last line of treatment is no evidence of disease, complete or partial response, or stable disease. Prior PARPi treatment is required for patients with a BRCA mutation. Patients who received bevacizumab in combination with their most recent platinum containing regimen are excluded. Patients are randomized 2:1 to UpRi 30mg/m2 or placebo, given IV Q4W. The primary endpoint is PFS assessed by BICR, with key secondary endpoint of OS. UP-NEXT is conducted in collaboration with GOG(3049) and ENGOT(Ov71-NSGO-CTU). Approximately 350 patients will be enrolled globally. NCT05329545. Clinical trial information: NCT05329545 .
Genome sequencing-based prognosis, mutational analysis, and survival rate of clear cell renal cell carcinoma.
Authors: Lisa Joy Centeno, Hai Pan, Preeti Malik, Tehmina Hashim, Olia Poursina, Lorena Antonella Velez Diaz, Samyukta Varma, Prachi Bapat, Arsh Chowdhary, Lean Alkhatib, Urvish Patel, Prasannalaxmi Palabindela, Kartik Kalra, Ashish Patil, Geetika Kukreja
Journal: Journal of Clinical Oncology (2023)

e16543 Background: The clear cell renal cell carcinoma (ccRCC) is the most prevalent genitourinary cancer, and carries a poor prognosis. Information regarding whole genome sequencing, a prognostic prediction system, and overall survival in ccRCC is limited. While loss of VHL is commonly implicated in ccRCC, two genes indicated in other cancers, SDHD and ARID1A, have limited literature on their correlation to ccRCC. Hence, we aimed to analyze the genomic profile, epidemiological characteristics and overall survival of ccRCC. Methods: We utilized cBioPortal cancer genomics [The Cancer Genome Atlas (TCGA) PanCancer Atlas, TCGA Firehose Legacy, and TCGA Nature 2013] to study the genetic mutations associated with ccRCC. Epidemiological characteristics and genetic profiles were evaluated, and a query was generated to calculate 5 year and 10 year survival rate with the most common mutations. Log-rank test and Kaplan–Meier estimator were used in analyzing the survival function. Patients with two or more overlapping mutations (72) were excluded. Results: We identified 761 patients with ccRCC, out of which 442 had primary ccRCC with all demographic details available. 65.8% were males, 58.1% were Caucasian, and 7.2% were African American. Majority of patients (199) were between the ages of 50-65 years. 286 (64.7%) were alive and 156 (35.3%) were deceased. The common mutations associated with reduced survival were VHL, BAP1, SDHA, SDHD, and ARID1A. Median survival of patients with VHL, BAP1, SDHA, SDHD, ARID1A mutations was 118.85, 93.04, 40.70, 2.04, and 6.02 months respectively in comparison with unaltered mutation group (78.44 months) (p &lt; 0.0001). (Table 1) Survival was lowest amongst SDHD [2.04 months] and ARID1A [6.02 months]. (p = 3.26e-10). In survival analysis, SDHD and ARID1A were associated with lowest survival after initial diagnosis at 60 months (Figure 1) and 120 months (Figure 2). (p = 2.592e-3). Conclusions: Our study found that SDHD, ARID1A, and SDHA genes were associated with the worst prognosis in ccRCC with median survival of 2.04, 6.02, and 40.70 months. This study may provide insight for targeted therapies for ccRCC and improve the prognosis of these patients. [Table: see text]